P22phox confers resistance to cisplatin, by blocking its entry into the nucleus.

Chih-Chang Hung,Chang-Shen Lin,Tzyh-Chyuan Hour,Jeff Yi-Fu Chen,Chen-Yu Chien,Wei-Fan Chiang,Chi-Hua Chang,Ling-Feng Wang,Hau-Ren Chen,Jenq-Yuh Ko

doi:10.18632/oncotarget.2893

Abstract

Cisplatin (CDDP) is a potent chemotherapeutic agent but resistance to the drug remains a major challenge in cancer treatment. To evaluate the efficacy of CDDP in oral squamous cell carcinoma (OSCC), we found that p22phox was highly expressed in CDDP-resistant OSCC specimens. Knockdown of p22phox sensitized OSCC cell lines to CDDP (P < 0.05). Stable overexpression of p22phox augmented CDDP resistance, as evidenced by the significantly higher IC50 values. This cytoprotective effect was attributed to the abrogation of CDDP-induced apoptosis. Akt phosphorylation was increased in p22phox stable lines. However, blocking PI3K/Akt pathway only partially restored CDDP-induced apoptosis. In addition, the overexpressed p22phox in OSCC cells exhibited cytoplasmic localization with enhanced perinuclear expression, consistent with the localization pattern in OSCC specimens. Remarkably, CDDP entry into the nucleus was severely impaired in p22phox-overexpressing cells (P < 0.001), and cytoplasmically accumulated CDDP was co-localized with overexpressed p22phox. This was supported by decreased CDDP-DNA adduct formation and delayed chk1-p53 signaling activation. Together, overexpression of p22phox sequestered CDDP and caused defective CDDP entry into the nucleus, significantly attenuating CDDP-induced apoptosis. Such diminished apoptosis was further abolished by p22phox-activating PI3K/Akt pathway. Our work has suggested a novel biomarker and insight into the mechanism of CDDP resistance.

Highlights

NADPH oxidases are a major source of reactive oxygen species (ROS) production in phagocytic leukocytes and in many non-phagocytic cells [1]
The NOX family NADPH oxidases and the key modulator p22phox have been implicated in cancer development [4,5,6, 18], it is still unknown about their role in cancer drug resistance
Since NADPH oxidases are the major source of ROS production, we previously used p22phox as the marker to investigate the correlation between ROS and oral carcinogenesis

Summary

Introduction

NADPH oxidases are a major source of reactive oxygen species (ROS) production in phagocytic leukocytes and in many non-phagocytic cells [1]. P22phox is one of the regulatory proteins whose major function is to stabilize the NOX enzymes to which it binds. This is supported by the studies showing that p22phox down-regulation results in decreased activity of several NOX enzymes [2, 3]. There is evidence that NADPH oxidases are the major sources of ROS in oral squamous cell carcinoma (OSCC) [6]. It is unknown whether p22phox has an impact on the treatment of OSCC

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Results

Conclusion